Selective androgen receptor degrader (SARD) to overcome antiandrogen resistance in castration-resistant prostate cancer

In patients with castration-resistant prostate cancer (CRPC), clinical resistances such as androgen receptor (AR) mutation, AR overexpression, and AR splice variants (ARVs) limit the effectiveness of second-generation antiandrogens (SGAs). Several strategies have been implemented to develop novel antiandrogens to circumvent the occurring resistance. Here, we found and identified a bifunctional small molecule Z15, which is both an effective AR antagonist and a selective AR degrader. Z15 could directly interact with the ligand-binding domain (LBD) and activation function-1 region of AR, and promote AR degradation through the proteasome pathway. In vitro and in vivo studies showed that Z15 efficiently suppressed AR, AR mutants and ARVs transcription activity, downregulated mRNA and protein levels of AR downstream target genes, thereby overcoming AR LBD mutations, AR amplification, and ARVs-induced SGAs resistance in CRPC. In conclusion, our data illustrate the synergistic importance of AR antagonism and degradation in advanced prostate cancer treatment.


Sample-size estimation
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Replicates
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The RNA sequence data could be found in the following link. subHRA001356(title: Selective androgen receptor degrader (SARD) to overcome antiandrogen resistance in castration-resistant prostate cancer, bioProject accession: PRJCA005389) is checked OK and released. The assigned accession of the submission is: HRA000921, which can be cited in your publication. Please access it from the following link: https://bigd.big.ac.cn/gsa-human/browse/HRA000921 The in silico screening was perform once (the details were shown as the Methods and Fig S1)

Statistical reporting
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Group allocation
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The group allocations were described in the "Methods" part.
The figures or tables for which source data files have been provided accompany with the submission.